[Synthesis of 1-butyl-3,5-bis-(pyridinemethyl)-piperidone-4 and 1-butyl-3,5-bis-(4-pyridinemethyl)-piperidone-4].
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Piperidines↗
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Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors.
The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)- (cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleuci namide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)- [(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5- methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.
Benzazepines↗
Biosynthesis of 5-aminopentanoic acid and 2-piperidone from cadaverine and 1-piperideine in mouse.
1-Piperideine, 5-aminopentanoic acid, and its lactam, 2-piperidone, were identified as metabolites of cadaverine in 10,000 g mouse liver supernatants to which diamine oxidase had been added. Both metabolites were also found when the cadaverine metabolite 1-piperideine was incubated with the preparation which suggested that 1-piperideine is an intermediate in the formation of 5-aminopentanoic acid and 2-piperidone. Identification of the metabolites was based on gas chromatography-mass spectrometric analysis in comparison to authentic standards. Mouse brain homogenates converted 1-piperideine to 5-aminopentanoic acid. The results suggest that the metabolic fate of cadaverine may provide precursors of pharmacologically active analogues of GABA.
Amine Oxidase (Copper-Containing)↗
Enhancing effect of piperidone derivatives on the percutaneous absorption of indomethacin.
Following our previous demonstration that Azone and 2-n-alkylcyclohexanones enhanced the percutaneous absorption of indomethacin, six 1-n-alkylpiperidones were prepared and examined as potential transdermal absorption enhancers. In vitro skin experiments showed that indomethacin absorption enhancement was related to the lipophilicity of the enhancer, and that 1-n-dodecyl piperidone caused the greatest enhancement. The structure of this piperidone is similar to that of Azone, and both compounds had similar lipophilicity and drug absorption enhancement activity. We suggest that they act in the same way by decreasing diffusional resistance in the stratum corneum, and so modifying the hard barrier of the stratum corneum.
Animals↗
[Pyrrolidone and piperidone derivatives with antihistaminic and antianaphylactic activities. Synthesis and pharmacological study].
The preparation of several derivatives to oxatomide (A), with the benzimidazolinone moiety replaced by another heterocyclic residue is described. In some cases changes to the basic chain of (A) were also considered. All the new compounds were evaluated as antihistaminics (H1) and antianaphylactics. The derivatives where the heterocyclic moiety was an unsubstituted or phenylsubstituted 2-pyrrolidone or 2-piperidone residue showed antihistaminic and antianaphylactic activities similar to those of oxatomide while modification of the basic side chain with elimination of the benzhydryl group, gave a complete loss of activity. The pharmacological screening was completed by the evaluation of the barbiturate induced sleep prolongation and of acute toxicity.
Anaphylaxis↗
3-Amino-2-piperidone in the urine of patients with hyperornithinemia.
3-Amino-2-piperidone, a delta-lactam of ornithine, has been detected in the urine of a number of patients with hyperornithinemia. The distinctive yellow colour formed with a ninhydrin-cadmium reagent should help in the detection of hyperornithinemia by urinary chromatography.
Adolescent↗
Gramicidin S synthetase. Stability of reactive thioester intermediates and formation of 3-amino-2-piperidone.
The reactive thioester complexes of gramicidin S synthetase with substrate amino acids and intermediate peptides are slowly hydrolyzed in neutral buffer solutions under mild conditions. Fully active enzyme is recovered. These processes are strongly accelerated by certain thiol protective agents. In the presence of 1 mM dithioerythritol the half-life times of these hydrolysis reactions are in the range of 1-90 h at 3 degrees C. The thioester complex of gramicidin S synthetase 2 (GS2, the heavy enzyme) with the tripeptide DPhe-Pro-Val is distinguished by the highest stability of all these intermediates. A different decomposition pattern is observed for the thioester complex of GS2 with LOrn. Here 3-amino-2-piperidone (cyclo-LOrn) is formed in a rapid cyclization reaction. This product specifically blocks the activation center of GS2 for LOrn at the thioester binding site. All other activation reactions of gramicidin S synthetase are unaffected. A procedure for a specific labelling of the reaction centers of the multienzyme is outlined.
Amino Acid Isomerases↗
Evaluation of some N-acyl analogues of 3,5-bis(arylidene)-4-piperidones for cytotoxic activity.
The synthesis of fourteen N-acyl derivatives of two 3,5-bis(arylidene)-4-piperidones was accomplished and these compounds were evaluated against L1210 leukemia cells in vitro. With one exception, the compounds had IC50 values of less than 10 microM and six of them had IC50 figures in the 0.2-0.6 microM range which were comparable to a reference drug melphalan. Twelve of the sixteen compounds showed specificity for human leukemia cell lines in the NCI in vitro screen. Studies using 1H NMR spectroscopy revealed that solutions of three N-acetylated compounds underwent deamination and possibly other reactions, the deaminated product itself being unstable in the solvent used.
Animals↗
3,5-Bis-arylidene-1-methyl-4-piperidone methohalides and related compounds with activity against L 1210 cells and DNA binding properties.
A series of 3,5-bis-arylidene-1-methyl-4-piperidone methohalides 2 and two related analogues in general demonstrated activity against L 1210 leukemia cells in vitro and bound to a synthetic DNA, poly[d(AT)]. Plots of various physicochemical constants of the aromatic substituents in series 2 versus the IC50 figures revealed correlations between the aryl MR and pi values but not the sigma constants. The delta Tm values of six members of series 2 were correlated with the MR figures of the aryl substituents but not the sigma nor pi values of the aromatic atoms and groups. Some suggestions for future molecular modification with a view to increasing cytotoxicity are presented.
Animals↗
3,5-Bis-benzylidene-4-piperidones and related compounds with high activity towards P388 leukemia cells.
3,5-Bis(benzylidene)-4-piperidones and related compounds were prepared and found to have between 100 and 9700 times the activity of N,N'-bis(2-chloroethyl)-N-nitrosourea towards P388 leukemia cells. The shapes of six of these molecules--determined by X-ray crystallography--were compared, but no correlation between the stereochemistry of the molecules or their electronic properties and cytotoxicity was apparent. Molecular modification of the compounds by forming two mono-benzylidene compounds, a related acyclic derivative and an N-acyl compound resulted in diminished but retained high cytotoxicity. Two representative compounds lowered glutathione levels of liver following their intraperitoneal injection into mice. Two quaternary ammonium compounds were shown to bind in the minor groove of DNA, while four related non-quaternary ammonium derivatives did not demonstrate this property. We conclude that the modes of action of these highly cytotoxic compounds include alkylation of cellular thiols and DNA binding, but interference with other biochemical processes is also probably involved.
Animals↗
Synthesis of 3-(4,4-dimethyl-2-piperidon-6-yl)methyl-2-pyrazoline derivatives.
The results of studies of condensation of 1-(4,4-dimethyl-2-piperidon-6-yl)-4-phenyl-3-buten-2-one and its derivatives substituted in the benzene ring (R = 4-CH3 and R = 4-Cl) with hydrazine and its methyl or phenyl derivative are described. Compounds 2a, 2c and 2g were tested for their possible action on the central nervous system. Two drugs: 2c and 2g decreased locomotor activity. None of the examined compounds inhibited the reserpine-induced hypothermia, 5-HT syndrome and convulsions induced by pentetrazole in mice. Compound 2c injected only intraperitoneally depressed the number of the writhing episodes induced by p-phenylbenzoquinone.
5-Hydroxytryptophan↗
Condensation of 1-(4,4-dimethyl-2-piperidon-6-yl)-2-propanone with benzaldehyde derivatives.
Condensation of 1-(4,4-dimethyl-2-piperidon-6-yl)-2-propanone with benzaldehyde derivatives and with cinnamic aldehyde was investigated. Generally, alpha, beta-unsaturated ketones with structures of the (E) -chalcone type were formed. The biological activity of the compounds, particularly given orally, seems to be negligible.
Analgesics↗
[Synthesis of antiproteolytically active 3,5-bis(4-amidinobenzyl)- and 3,5-bis(4-amidinobenzylidene)piperidone-(4) derivatives (author's transl)].
Because of the good inhibitory effects of some alpha, alpha'-bis (amidinobenzylidene)cycloalkanoes and of their hydrogenation products on serine proteinases, the authors prepared structurally analogous bisamidines of heterocycloalkanones. To obtain 3,5-bis(4-amidinobenzyl)-N-benzoylpiperidone-(4), N-benzoylpiperidone-(4) was condensed with 4-cyanobenzaldehyde in concentrated phosphoric acid. The resultant 3,5-bis(4-cyanobenzylidene)-N-benzoylpiperidone-(4) was reduced with zinc-glacial acetic acid, and the reduction product was converted into the respective bisamidine by means of the Pinner method. 3-(4-Cyanobenzylidene)-5-(4-aminocarbonylbenzylidene)-N-benzoylpiperidone-(4) was isolated as a by-product of the condensation of N-benzoylpiperidone-(4) with 4-cyanobenzaldehyde. To prepare 3,5-bis(4-amidinobenzylidene)-N-benzoylpiperidone-(4), N-benzoylpiperidone-(4) was condensed with 4-amidinobenzaldehyde hydrochloride in concentrated phosphoric acid. The resultant bis-dihydrogen phosphate was converted into the bis-hydrochloride by treatment with methanolic hydrochloric acid solution in the cold, and debenzoylated to 3,5-bis(4-amidinobenzylidene)piperidone-(4) trihydrochloride on heating with methanolic hydrochloric acid solution.
Amidines↗
ESR correlation times of 2,2,6,6-tetramethyl piperidone-N-oxyl (Tempone) in solutions of hemoglobin A and hemoglobin S.
Correlation times for the tumbling motion of the spin probe 2,2,6,6,-tetramethyl piperidone-N-oxyl (Tempone) were obtained in the presence of different concentrations of oxyhemoglobin A, oxyhemoglobin S, and deoxyhemoglobin S and compared to the viscosity of non-gelling hemoglobin solutions. Reorientational motion (or tumbling) of Tempone in gelled solutions of deoxyhemoglobin S is as great as that in non-gelled hemoglobins of the same total concentration. It is concluded that the gel does not exclusively partition Tempone into an aqueous phase of lower solute concentration after gel formation. The gel at room temperature is a highly mobile and dynamic structure on the microscopic level.
Electron Spin Resonance Spectroscopy↗
The effect of 3-methyl substitution on the carcinogenicity of nitroso-4-piperidone.
The carcinogenic activity of the 3-methyl derivative of nitroso-4-piperidone was compared with that of the compound without the methyl group, by chronic administration to rats at equimolar doses in drinking water. Nitrosopiperidone induced both liver and esophageal tumors, whereas the 3-methyl derivative induced only tumors of the esophagus in a much shorter time.
Animals↗
Nucleophilic and bifunctional catalysis. Mechanism, reactivity, and transition-state structure in the hydrolysis of 2-chloro-4-isopropylamino-6-cyclopropylamino-s-triazine by N-hydroxysuccinimide and 1-hydroxy-2-piperidone.
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Catalysis↗
Structure of (3S)-3-tert-butyloxycarbonylamino-2-piperidone.
C10H18N2O3, Mr = 214.27, monoclinic, P2(1), a = 15.515 (2), b = 6.730 (1), c = 12.541 (2) A, beta = 113.6 (2) degrees, V = 1200.0 A3, Z = 4, Dx = 1.186 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.54 cm-1, F(000) = 464, T = 295 K. The final R value for 1611 observed (3139 unique) reflections is 0.055. In both the independent molecules A and B of the asymmetric unit of the title compound, the conformation of the urethane moiety is trans. The lactam group of molecule A is non-planar, the C(9)-N(2)-C(10)-C(6) torsion angle being 12.4 (14) degrees. One main difference between molecules A and B is in the value of the phi[C(5)-N(1)-C(6)-C(10)] torsion angle [52.3 (11) degrees for molecule A while -86.5 (10) degrees for molecule B] as a consequence of a rotation of the ring relative to the tert-butyloxycarbonylamino substituent. A second major difference is the delta-lactam ring conformation which is approximate half-chair for molecule A while boat for molecule B.
Chemical Phenomena↗
Lactams. XXIV. Alkaline hydrolysis of 1-benzyl-2-piperidone derivatives: application to cis-trans isomerization of the 5-ethyl-2-oxo-4-piperidineacetic acid system.
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Benzyl Compounds↗